Combination Hormone Replacement Therapy (HRT) and Melatonin to Prevent and Treat Mammary Cancer

ABSTRACT

A combination hormone and melatonin therapy is provided to reduce the risk of developing, or to reduce the severity of, breast cancer by administering at least one estrogen hormone and optionally at least one progesterone-receptor-binding compound or composition and melatonin together, preferably at normal bed time.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuing application of U.S. Ser. No. 12/804,341filed Jul. 20, 2010, which claims priority to, and incorporates hereinby reference, U.S. Provisional Patent Application No. 61/273,165 filedJul. 31, 2009.

BACKGROUND OF THE INVENTION

1. cl Field of the Invention

With an emphasis on women's overall health, the invention pertains toimproved prevention and treating agents, and methods for preventing andtreating, mammary cancer.

2. Description of Related Art

In addressing mammary (breast) cancer, it is important to address awoman's overall health besides just the prevention or treatment ofcancer. The ability of peri-menopausal women to treat menopausalsymptoms while also decreasing their risk of breast cancer is importantin improving quality of life as well as in reducing the risk of otherage-related diseases. As hormone replacement therapy is currentlyrecommended only for short-term use for women with severe menopausal andperi-menopausal symptoms, many women struggle through problems includingbut not limited to hot flushes, vaginal dryness, irritability, andincontinence. Estrogen therapy has been the most effective therapy todate to help with all those symptoms as well as in protecting againstosteoporosis.

At the same time, prevention and treatment of breast cancer is importantin improving both health and quality of life. Certain treatments whichdo not fall within the typical bounds of traditional chemotherapy haveshown significant promise, such as the oral administration of melatonin.Melatonin was, prior to the present invention, known to exhibitdistinctive anti-mammary-cancer effects, and previous studies have shownthat enhancing the nocturnal surge in melatonin, by administeringmelatonin at bedtime or during the night, has been more protectiveagainst the development of mammary cancer than supplementing melatoninin a continuous manner. There has been a general consensus in themammary cancer field, however, that melatonin itself is not an adequatepreventive or treatment for mammary cancer, despite its positiveeffects. Even though other recent strides in breast cancer treatmenthave been favorably impressive a need still remains for a particulartherapy which can both prevent or treat mammary cancer at the same timethe treatment reduces or eliminates the symptoms of peri-menopause ormenopause, ideally while presenting risks or side effects within thegeneral bounds of those of melatonin Despite this need, the prevailingwisdom at this writing (not including the present invention) is thattreating menopause, and preventing or treating breast cancer, areseparate disciplines. However, logically, if there were a safe andeffective way of treating menopause and at the same time preventing ortreating breast cancer in the same therapeutic regimen, such a therapywould represent a significant—even historic—advance in women's healthcare.

SUMMARY OF THE INVENTION

In order to meet this need, the present combination therapy both treatsthe symptoms of peri-menopause or menopause and simultaneously acts toprevent or to treat mammary cancer in a patient—particularly (but notnecessarily only) in a female patient aged 40 or older. The combinationtherapy includes honnone replacement therapy (HRT) and melatonin asdiscussed below. (HRT is sometimes revised to MRT in current usage,signifying “menopause replacement therapy” inasmuch as the term HRT isnot specific for women or menopausal symptoms. Having said that, to theend that the present therapy can be administered to HRT both the HRT andMRT terms are apropos.) In giving both HRT and melatonin together, it ispossible to reduce mammary cancer incidence or to treat existing mammarycancer and also to treat the symptoms of peri-menopause or menopause, atthe same time, and both to a significant degree. The HRT typicallyincludes an estrogen at about the currently recommended dose, aprogesterone-receptor-binding compound at about half the currentlyrecommended dose, and melatonin at the currently recommended dose formelatonin administered alone, but with the melatonin administered atbedtime or during the night.

BRIEF DESCRIPTION OF THE DRAWING(S)

FIG. 1A is a line graph showing age of primary mammary tumor onset andincidence between control (CN) vs. melatonin (UM) groups.

FIG. 1B is a line graph showing age of primary mammary tumor onset andincidence between control vs. HRT (HRT/V) groups.

FIG. 1C is a line graph showing age of primary mammary tumor onsetbetween HRT vs. HRT plus melatonin (HRT/M) groups.

FIG. 1D is a line graph showing age of primary mammary tumor onsetbetween control vs. HRT plus melatonin (HRT/M) groups.

FIG. 2 is a bar graph showing decrease if any in total tumor volume inthree groups of mice upon administration of melatonin, HRT, and HRT plusmelatonin, in contrast with the fourth group of control mice.

FIG. 3A is a bar graph showing the result that mice exposed to hormonereplacement therapy with melatonin experienced dramatic change in RNAexpression in the lower mammary gland; FIG. 3B is a bar graph showingthe result that mice exposed to hormone replacement therapy withmelatonin experienced dramatic change in RNA expression in the lowermammary gland.

DETAILED DESCRIPTION OF THE INVENTION

The present combination therapy both treats the symptoms ofperi-menopause or menopause and simultaneously acts to prevent or totreat mammary cancer in a patient—particularly (but not necessarilyonly) in a female patient aged 40 or older. The combination therapyincludes hormone replacement therapy (HRT) and melatonin as discussedbelow. In giving both HRT and melatonin together, it is possible toreduce mammary cancer incidence or to treat existing mammary cancer andalso to treat the symptoms of peri-menopause or menopause, at the sametime, and both to a significant degree. The HRT typically includes anestrogen at about the currently recommended dose, aprogesterone-receptor-binding compound at about half the currentlyrecommended dose, and melatonin at the currently recommended dose formelatonin administered alone, but with the melatonin administered atbedtime or during the night

To simplify compliance, the combined active agents may be compoundedtogether in an oral dosage form intended for administration at bedtime.A typical oral dosage form could contain 0.5 mg 17 β-estradiol (E₂), 50mg of progesterone (P₄) and 5 mg melatonin, together with customarypharmaceutically acceptable excipients and diluents, in a form typicallyintended for oral administration such as a tablet, a capsule, a caplet,a lozenge, a fast-dissolve strip, or a piece of chewing gum, withoutlimitation. The oral dosage form may also be a solution, containing oneor more of the above-described active agents or other similar activeagents described below; if the active agents are in separate solutionsthe combination therapy may be implemented by administering one or moresolutions to the patient at the same time. The combined active agentsmay also be used as constituents or additives in food supplementsincluding but not limited to food bars and supplement drinks, althoughmost usually the combined active agents are given with minimized if anyadditional calories due to the optimal bedtime administration of atleast the melatonin component. Daily dosage variations for theabove-described oral dosage form include the combination of 0.1-0.9 mg17 β-estradiol (E₂) with 10-90 mg of progesterone (P₄) and 1-9 mgmelatonin, more preferably 0.2-0.9 mg 17 β-estradiol (E₂) with 20-80 mgof progesterone (P₄) and 2-8 mg melatonin, and most preferably 0.4-0.6mg 17 β-estradiol (E₂) with 40-60 mg of progesterone (P₄) and 4-6 mgmelatonin. Typically these dosages may be adjusted, according to theskill in the art, to accommodate patients whose body weights varysignificantly from an average body weight. The active agents of thepresent invention, as well as their compounding and oral dosage formpreparation generally, are already known in the art, and the presentinvention is directed to the improvement of coadministration of HRT andmelatonin in the improved therapies disclosed herein.

The estrogen and progesterone components of the above-describedexemplary formulation each represent an active agent chosen from theclasses of a) estrogens and b) progesterone-receptor-bindingcompositions. Estrogens include, without limitation, estradiol, ethinylestradiol (EE), estriol, estrone, conjugated equine estrogens (CEE) andprogesterone-receptor-binding compound include, without limitation,progesterone, medroxyprogesterone acetate; levonorgestrel,norethindrone, norethindrone acetate, norgestimate or other progestins.The term “progesterone-receptor-binding compound” is used to avoidgeneral confusion among the nomenclature of progestins/progesterone,because any compound (or composition) which binds to the progesteronereceptor is contemplated for use in the present invention. In the oralformulation, 17 β-estradiol, progesterone and melatonin are preferred.The two constituents together may even be “CEE/MPA” (conjugated equineestrogen/medroxyprogesterone acetate) already known in the art, withoutreducing the progesterone proportionately (because there is no easy wayto do so).

As described above, when 17 β-estradiol, progesterone and melatonin areadministered in the practice of the invention, oral administration andoral dosage forms are advantageous for ease of administration andcompliance enhancement. However, the various estrogens,progesterone-receptor-binding compounds (or compositions) and melatoninmay be given by a wide variety of routes of administration and theirdosage ranges will vary accordingly. A good route of administration forcertain estrogens is transdermal (via a patch known in the art) to avoidthe hepatic first pass effect and certain resultant metabolites whichmay themselves promote breast cancer. Synthetic hormones will generallybe administered via the oral route. Transmucosal delivery methods(vaginal delivery, sublingual, buccal, etc.) may be used with thepresent invention, as may implants, parenteral administration, or anyother route of administration, with the understanding that for practicalsimplicity and patient compliance oral administration is generallypreferred.

Overall, those skilled in the art understand that in order to reach thetherapeutic blood levels expected with administration of 17 β-estradiol,progesterone and melatonin described above, adjustment must be made forroute of administration and other dosing considerations. The followingcomments are explanatory and orient the reader to certain considerationsalready known in the art, to determine dosing by other routes ofadministration. When given transdermally according to the prior art, 17β-estradiol is administered at 0.025 mg to 0.1 mg per day for Climara(as an nonlimiting example). The prior art Climara Pro HRT patch uses 17β-estradiol at 0.045 mg/day and levonorgestrel at 0.015 mg/day. Othersynthetic oral progestins are more potent and absorb better thanprogesterone so their doses are considerably lower than a comparableprogesterone dose. CEE/MPA HRT (oral) currently is given at therecommended lowest dosages of 0.3 mg CEE+1.5 mg MPA. Therefore, reducingeven the 0.3/1.5 proportion so that the progesterone approaches halfthat amount is in keeping with the present invention. PREMPRO® 0.3mg/1.5 mg therapy consists of a single tablet containing 0.3 mg of theconjugated equine estrogens (CEE) found in Premarin® tablets and 1.5 mgof medroxyprogesterone acetate (MPA) for oral administration. PREMPRO0.45 mg/1.5 mg therapy consists of a single tablet containing 0.45 mg ofthe conjugated estrogens found in Premarin tablets and 1.5 mg ofmedroxyprogesterone acetate for oral administration. Again, thesetypical dosage forms available at this writing help to illustrate how toimplement the present invention with a typical dose of an estrogenaccompanied by an approximately half-typical dose of progesterone (orsubstitute) and to illustrate what “half” means in the context ofcurrently typical therapies and commercial dosage forms for which theinvention preferably includes half the typical amount of progesterone orequivalent. PREMPRO 0.625 mg/2.5 mg therapy consists of a single tabletcontaining 0.625 mg of the conjugated estrogens found in Premarintablets and 2.5 mg of medroxyprogesterone acetate for oraladministration. By taking any of these currently commercial products ortheir equivalents and reducing the progesterone-receptor-bindingcompound (composition) to about half, adding melatonin and administeringat night, one can practice the present invention. The best iterationsare the dedicated dosages forms including a single pill, solution orother construct that is administered to the patient as a single dosageform.

In line with the previous paragraph, when 17 β-estradiol andlevonorgestrel are combined in a dosage form for the treatment of thepresent invention, the ratio by weight of 17 β-estradiol tolevonorgestrel is about 5.5:1 to 6.5:1, preferably about 6:1. However,because the doses of progesterone must be higher than those of syntheticprogestins due to absorption issues, when CEE is combined withmedroxyprogesterone acetate (MPA) the ratio by weight of CEE to MPA isabout 1:2-2.5. Having said that, however, it is possible to practice theinvention by taking any typical hormone replacement therapy known in theart at this writing and containing an estrogen or equivalent and aprogesterone or equivalent, and roughly halving the dosage of theprogesterone or equivalent component.

The estrogen component is usually adjusted relatively higher to give thebest relief for women with symptoms and the progestogen also needs to beadjusted to provide more uterine protection. So if just estrogen isgiven (ERT, or estrogen replacement therapy), for women without auterus, the dosage can vary without needing to consider the progesteronedose. A common estrogen given for HRT (oral) and oral contraceptives isethinyl estradiol (EE), such as in femHRT (2.5 mcg EE+0.5 mgnorethindrone or 5 mcg EE+1 mg norethindrone). Progesterone is notavailable as a patch, since the dose of progesterone needs to be higherthan progestins since progesterone is less potent. It is available increams, such as vaginal or other topical creams. Apart from the singledosage form goal for compliance and convenience, the medically optimalway to administer the combinational therapy is to administer 17β-estradiol by patch and progesterone and melatonin orally in a singlepill, even though the progesterone-receptor-binding compound may beadministered in a cream such as a vaginal cream when desired. In pillform, the progesterone and 17 β-estradiol generally have to bemicronized to give optimal delivery. A particularly preferred dosageform is therefore a “one tablet” therapy comprising micronized 17β-estradiol plus micronized progesterone plus melatonin for oraladministration in either a cyclic or continuous dosing regimen. Forexample, if a month's aggregation of pills includes hormone free pillsto approximate a monthly cycle, the hormone free pills still include themelatonin, and all the pills for administration throughout the cycle areintended for bedtime or nocturnal administration. It should be borne inmind that the addition of nocturnal melatonin allows the dosage of theprogestational agent to be reduced below the minimum level required toprotect the uterus in the absence of melatonin supplementation.

The melatonin constituent of the present therapy is described herein asbeing administered “at bedtime” or “at night.” These expressions areshorthand for the idea of administering the melatonin to correspond withthe sleep cycle of the patient—so for a night shift worker, theadministration time for the melatonin should be modified to correspondto his or her actual bedtime (presumably in the morning) because workersexposed to light all night have their biological clocks disrupted.Ideally, then, the melatonin component of the invention is administeredto the patient at the same time as the patient will naturally experiencehis or her own highest natural melatonin levels or at least thebeginning of any natural melatonin surge. As described elsewhere hereinany dose between 1-9 mg is within the scope of the invention forprevention of breast cancer, with 3-9 mg per day being preferred forprevention, but it should be understood that up to 50 mg melatonin maybe indicated for sole or complementary cancer treatment.

Some important variations on the methods and formulations disclosedherein are that a) for certain patients (women lacking a uterus,primarily), the hormone supplementation may at times be estrogen plusmelatonin alone, and b) in certain patients who have been diagnosed withbreast cancer, the melatonin therapy alone should continue withouthormone supplementation until the patient is cancer free. The estrogenand melatonin together may beneficially be given to women without auterus, because the progestogen component is used in part to protect theuterine tissue during the hormone replacement therapy. Having said that,there will be times when administration of progesterone-receptor-bindingcomponent and melatonin alone, without estrogen, will be indicated andthis is within the scope of the present invention also. These periodicor midstream alterations in the ongoing dosing of the patient areconsistent with the overall goal of supplementing all three of estrogen,progesterone-receptor-binding compound and melatonin at all points inwhich the patient is a proper recipient of such therapy. Thismodification is important to understand in the context of the presenttherapy's being an ongoing therapy for many patients, beneficially beinggiven for years or decades of improved health and quality of life.

Collectively, the results reported in the Examples below, plus otherdata not reported here, demonstrate not only that all threetreatments—melatonin, HRT, and melatonin+HRT—have protective effects onmammary tumor development and/or progression, but that the combinationHRT plus melatonin preventive therapy gives new and unexpected resultscompared to either preventive therapy given alone or even considered forits additive effects in combination. Indeed, in data not reported hereit was confirmed that when a half dose of progesterone (compared torecommended current levels) was given with 17 β-estradiol and melatonin,the combination prevented unwanted increase in uterine weight despitethe progesterone half-dose. Moreover, by reducing progestin to abouthalf of currently recommended levels, the combination HRT plus melatonintherapy not only gave no adverse effects on mammary cancer risk but abeneficial effect was even observed by reducing incidence and delayingtumor onset. In addition, for mammary tumors that did occur, tumorgrowth and metastatic incidence were also suppressed compared tountreated mice. At a minimum, the data reported below support that byusing estrogen and a reduced dose of a progesterone-receptor-bindingcompound, the adverse effects reported in a 2002 Women's HealthInitiative study may be avoided in women by undergoing the presentcombination therapy. When melatonin was added to the HRT, anti-cancerbenefits were detected both in reducing tumor development and inreducing progression (reduced incidence and delayed onset), so that HRTplus melatonin gave better preventive therapeutic effect on breastcancer than either HRT or melatonin administered alone. Therefore, thiscombination treatment is believed to be important for both theprevention and treatment of breast cancer in animal (mammalian) andhuman patients. These data are relevant to a common form of breastcancer, HER2+, which is aggressive and relatively more resistant totherapy than most other forms of breast cancer. As a preventive therapy,these data support the conclusion that upon combined administration ofHRT and melatonin according to the invention, fewer women will getbreast cancer and, for those that do, it will occur at older ages thanhad the present combination treatment been withheld. Moreover, even ifbreast cancer were detected while on this combination therapy, thetumors would be less likely to progress to metastatic disease and woulddo so, if at all, more slowly. Clearly, reducing metastatic disease ordelaying its onset while simultaneously ameliorating the symptoms ofperi-menopause or menopause, will have dramatic benefits to a woman'ssurvival and overall health, quality of life and life expectancy.

An important side benefit of nocturnal melatonin therapy in the contextof this invention is that, in addition to all the other benefits thepatient will experience, the patient will also enjoy the profoundbenefit of improved sleep. Since most peri-menopausal and menopausalwomen have sleep disturbances from symptoms or from the naturallydeclining level of melatonin with age, or both, melatoninsupplementation reverses these effects and improves sleep both for thepatient and for a spouse or partner sleeping next to or near thepatient. Melatonin augments the benefits of HRT by stimulating boneformation to prevent and reverse osteoporosis. It is no exaggeration tosay that when patients are given the therapy described herein,particularly women over age 40, they experience better sleep, betterwell-being, better cancer avoidance or at least delayed onset andreduced incidence of breast cancer, reduced or reversed osteoporosis,and amelioration of the myriad of symptoms of menopause andperi-menopause. The inventive combination is so important that it isdifficult to envision that its adoption will not be widespread, in partbecause the patients themselves will demand it.

Certainly the main population intended for the present treatment is thefemale population. However, even though men are reluctant to agree toadministration of estrogen or estrogen/progesterone (or equivalent)female hormones, the present invention does not preclude theadministration of the disclosed therapy to men as well as women incircumstances of need (see for example the next paragraph).

As a general consideration, the present invention is optimal forpatients having been diagnosed with, or at risk for,estrogen-independent breast cancer. Heretofore there has been a stigma—ade facto taboo—to the administering of estrogen to a breast cancerpatient unless the patient has estrogen-independent breast cancer, eventhough keeping estrogen available usually means that evennon-estrogen-independent breast cancer tumors are less aggressivenotwithstanding the possibility of the estrogen acting as a growthstimulant. The inventors believe that over time the above-mentionedtaboo will weaken or disappear, but in the meantime the invention hasparticular application to treating or preventing estrogen-independentbreast cancer. In particular, the combination therapy of the inventionis a good option for breast cancer survivors without any currentevidence of cancer because the combination therapy should reduce thechances of metastases and possibly even reduce the growth of anyundetected tumors. It should be borne in mind that anything that reducesthe most aggressive type of breast cancer, as the below datacorroborate, is relevant and important with respect to all breastcancer. Indeed, if the patient were to develop estrogen-dependent breastcancer in the presence of the instant HRT, the HRT would most likelykeep the cancer responsive to tamoxifen—thus providing an additionalbenefit to the invention. Finally, although the inventors believe thatthere may be particular benefits associated with administration ofnatural hormones rather than synthetic ones, it is also believed thatall of the estrogen and progesterone-receptor-binding compounds andcompositions will work in the context of the invention, that is, incombination with melatonin administration. In summary, the inventorsbelieve that a wide population of patients, including women, with allsorts of forms of breast cancer and particularly those in whom there isno breast cancer or in whom incipient breast cancer has not yet beendiagnosed, will ultimately be helped dramatically and sometimesimmeasurably by the treatments disclosed and claimed herein.

EXAMPLE 1

We studied the effects of the present combination therapy as follows. Wechose a mouse model, MMTV-neu mice, which express the neu oncogene thatmimics HER2+ breast cancer. In a population of mice, both melatonin andHRT were given orally to correlate with the dosage method in women,basing the dosing on diet based on the calories an average womanconsumes daily, namely, 1800 kcal, but adjusting for the small size andmetabolism of the mice. Estrogen +progestin HRT contained thebioidentical hormones 17 β-estradiol (E₂) at the currently recommendeddosage for women (0.5 mg/1800 kcal) and progesterone (P₄) at half of therecommended dose (50 mg/1800 kcal). For example, the daily mouse dosewould be less than 500 mcg progesterone (P₄). Melatonin was provided inthe drinking water at a concentration of 15 mg/L (dose equivalent to a 5mg tablet for women) only during the night to supplement the normalnocturnal surge in endogenous melatonin. Using drinking water ratherthan food to administer melatonin allowed the mice continual access tothe control and HRT diets, instead of just during the night (darkcycle).

Referring now to FIG. 1, survival curves are shown which represent theage of primary mammary tumor onset in weeks, on the x axis, and percentmammary tumor incidence on the y axis. FIG. 1 a represents age ofprimary mammary tumor onset and incidence between control (C/V) vs.melatonin (C/M) groups, with C signifying no hormone administration, Vsignifying no melatonin administration, and M signifying melatoninadministration. FIG. 1 b represents control vs. HRT (HRT/V) groups, withC signifying no hormone administration, V signifying no melatoninadministration, and with HRT signifying Hormone Replacement Therapy (inFigure lb, without melatonin, or “V”). FIG. 1 c represents the resultsof HRT/V versus HRT/M administration (M=melatonin) and FIG. 1 drepresents the results of CN versus HRT/M administration. The resultsfor the tumor studies showed a multitude of effects using nocturnallyadministered melatonin in combination with HRT on mammary tumor latency,growth and progression. No change in body weight occurred as a result ofthe treatments. Melatonin alone did not modify the latency or incidenceof mammary cancer in the neu mice (see FIG. 1 a). As shown in FIG. 1 b,the incidence and latency were not adversely affected by HRT alone,which is in marked contrast to the adverse effects reported in the 2002Women's Health Initiative study. FIG. 1 c represents HRT vs. HRT plusmelatonin; FIG. 1 d represents control versus HRT plus melatonin. Thecombination of melatonin with HRT resulted in a significant increase inlatency and decrease in incidence when compared to control animals, aseasily visible in FIG. 1 d. For control animals, the incidence ofmammary cancer was 44/57 (77%), 42/57 (74%) for melatonin-treated, 36/56(64%) for HRT-treated and 30/51 (59%) for HRT/melatonin treated. Thesedata suggest that the combined melatonin plus HRT therapy has preventiveaction on mammary tumor development both in neu mice and (concomitantly)in human subjects, particularly women patients, and the datasubstantiate the conclusion that the combined administration of HRT andmelatonin gives new and unexpected results as illustrated in FIG. 1 d.

EXAMPLE 2

As a result of the same study reported in Example 1, and with respect totumor growth, melatonin, HRT, and combinations thereof showed asignificant decrease in tumor weight and volume compared to controlanimals (FIG. 2). These data suggest that reduced tumor growth is apromising benefit of administration of all three active agents and inparticular that the co-administration of melatonin with HRT improves thedecreasing of total tumor volume compared to HRT given alone.

EXAMPLE 3

Mice exposed to hormone replacement therapy with melatonin, according tothe present invention, experienced dramatic changes in RNA expression(both upregulation and downregulation) in the lower mammary gland asdetermined by microarray analysis. However, melatonin alone resulted ina limited number of RNA expression changes. FIG. 3 reports aggregateddata regarding thousands of RNA fragments tested for over- orunder-expression of more than one and one-half times more or lessexpression than in control, for mice treated with C/C (no hormone, nomelatonin control), C/M (no hormone/melatonin), EMP/C (estrogen/midprogesterone (that is, half the recommended dose of progesterone, or 50mg (P₄)) but no melatonin) and EMP/M (estrogen/mid progesterone (thatis, half the recommended dose of progesterone, or 50 mg (P₄)) andmelatonin). The y axes of FIG. 3 a and FIG. 3 a are different, and showthat although many many RNA fragments or moieties (213) are upregulatedupon administration of EMP/M (FIG. 3 a), many many more RNA fragments ormoieties (776) are downregulated by EMP/M (FIG. 3 b). Moreover, theoverwhelming preponderance of the downregulation occurs with EMP/M andnot with either the hormone therapy or the melatonin therapy whenadministered without the other.

Although the invention has been described with particularity above, withspecial reference to specific materials and methods, the invention isonly to be limited insofar as is set forth in the accompanying claims.As non-limiting examples, the active agents of the present invention maybe added in suitable form (micronized, etc.) to a topical cream intendedfor application at night to the legs, arms, abdomen or even to the face.Women in particular in many cases are open to and even agreeable to theapplication of skin creams at bedtime and such a routine can enhancecompliance with the inventive dosing regimen. Dosing can be metered byplacing the cream-formulated ingredients in a metering dispenser, sothat a single “pump” of the dispenser represents a defined dose; twopumps is double the first one-pump dose, and so on.

1-12. (canceled)
 13. A method of suppressing Her2+ mammary cancer tumordevelopment in a patient in need of said suppression, comprisingadministering in unit dosage form an estrogen, aprogesterone-receptor-binding compound or composition, and melatonin,wherein said melatonin is administered to correspond with the sleepcycle of said patient and wherein said estrogen is 17 β-estradiol, saidprogesterone-receptor-binding compound or composition is progesterone,and wherein said 17 β-estradiol is administered via a route ofadministration to said patient in the amount corresponding to an oraldose of 0.1-0.9 mg per day, said progesterone is administered via aroute of administration to said patient in the amount corresponding toan oral dose of 10-90 mg per day and further wherein said melatonin isadministered via a route of administration to said patient in an amountcorresponding to an oral dose of between 1-9 mg per day.